Investigating the pathogenesis of urolithiasis through gut microbiome, plasma metabolome and inflammatory proteome: a mediation Mendelian randomization study.

backgroundUrolithiasis is a multifactorial systemic metabolic disease influenced by genetic, environmental, and dietary factors. Although previous observational studies have established strong links between the gut microbiome, plasma metabolome, inflammatory proteome, and urolithiasis, may be influenced by various confounding factors. This study aims to elucidate the causal relationships between gut microbiota (GM) and urolithiasis, and to investigate whether plasma metabolites and inflammatory proteins mediate this interaction.

methodsWe utilized publicly available dataset from genome-wide association studies (GWAS) to obtain data on GM, plasma metabolites, inflammatory proteins and urolithiasis. To elucidate the causal relationship between GM and urolithiasis, we conducted bidirectional Mendelian randomization (MR) analyses. Additionally, a two-step MR approach was applied to investigate whether GM contributes to the development of urolithiasis via plasma metabolites and inflammatory proteins, quantifying the mediation effect. Inverse variance weighting (IVW) was the primary method, with Bayesian weighted Mendelian randomization (BWMR), MR-Egger, and weighted median (WM) analyses used to ensure the robustness of our findings. Tests for horizontal pleiotropy and heterogeneity were conducted to confirm the reliability of the results. OUTCOME: MR analyses identified causal relationships between seven GM taxa and six metabolic pathways with urolithiasis, while urolithiasis induced changes in 13 GM taxa and five metabolic pathways. Additionally, 43 plasma metabolites (27 identified, 8 unidentified, and 8 metabolite ratios) and six inflammatory proteins were identified as potential mediators in the GM-urolithiasis connection. Through two-step mediation analysis, 13 causal pathways were identified. After excluding metabolic pathways and unidentified metabolites, we determined that galactonate and LAP-TGF-β1 mediate the relationship between Bacteroides faecis, Alistipes finegoldii, and urolithiasis, with mediation proportions of 16.99% (P = 0.0371) and 9.61% (P = 0.0469), respectively.

conclusionThe present MR analysis provides evidence supporting causal relationships between specific GM taxa and urolithiasis, with plasma metabolites and inflammatory proteins emerging as potential mediators.